Certain substituted cyclohexyl amines

ABSTRACT

The invention relates to cis cyclohexyl derivations of the formula R2 CH2 wherein R is hydrogen, methyl or ethyl and R2 is alkyl (C3 to C6), Cycloalkyl (C4to C9), bicycloalkyl (C7 to C10) or tricycloalkyl (C10 to C11). These compounds are used as intermediates in preparing N-acylcyclohexylamines, having utility as animal repellants.

United States Patent Knowles 1 Oct. 10, 1972 [54] CERTAIN SUBSTITUTED[56] References Cited CYCLOHEXYL AMINES UNlTED STATES PATENTS 1 lnvemorlRichard Knowles, Ockessin, 3,392,198 7/1968 Paulshock ..260/563 Del.

[73] Assignee: E. l. du Pont de Nemours and Com- Primary xaminer-LelandA. Sebastian pany, Wilmington, Del. Att0rneyllerbert W. Larson 22 F1 d:M 17, 1968 l l ay 57 ABSTRACT 21 Appl. No.: 730,198

The inventlon relates to us cyclohexyl derivations of Related US.Application Data the formula R CH s NHR,

[60] Dlvlsion of Ser. No. 635,304, April 20, 1967, H

which is a continuation-in-part Of wherein R is hydrogen, methyl orethyl and R is alkyl 574,499, g- 8, 1966, Sen N9 574,276, 0 to cCycloalkyl 0 m 0 bicycloalkyl c, to

1966- C or tricycloalkyl (C to C These compounds are used asintermediates in preparing N-acyl- {3 g cyclohexylamines, having utilityas animal repellants. [58] Field of Search...260/563, 563 R, 563 P, 563D; 10 Cl i N D i CERTAIN SUBSTITUTED CYCLOHEXYL AMINES CROSS-REFERENCEThis application is a divisional application of US.

Pat. application Ser. No. 635,304, filed Apr. 20, 1967,

which in turn is a continuation-in-part of U.S. Pat. applications Ser.No. 574,499, filed Aug. 18, 1966, and Ser. No. 574,276,filed Aug. 18,1966.

BACKGROUND OF THE INVENTION Application Ser. No. 532,544, filed Mar. 1,1966, now abandoned and Ser. No. 574,276, filed August 18, 1966 relateto compounds containing cyclohexyl ring structures and having utility asanimal repellants.

The present application is directed to those compounds useful asintermediates for'making the animal repellants described in applicationSer. Nos. 532,544 and 574,276.

SUMMARY OF THE INVENTION This invention relates to five classes ofintermediates for making N-acylcyclohexylamines.

More specifically, this invention refers to intermediates forsynthesizing potent animal inhalation irritant compounds of the formula:

( R O l N- R1 H R2--C H wherein following formulas:

wherein R is bicycloalkyl of seven through 10 carbon atoms ortricycloalkyl of 10 through 1 1 carbon atoms.

R is cycloalkyl of four through nine carbon atoms, cycloalkylalkyl offive through 10 carbon atoms,

bicycloalkyl of seven through 10 carbon atoms, or

tricycloalkyl of 10 through 1 1 carbon atoms.

wherein R is cycloalkyl of four through nine carbon atoms, bicycloalkylof seven through l0 carbon atoms, cycloalkylalkyl of five through 10carbon atoms, or tricycloalkyl of 10 through 1 l carbon atoms.

v w H wherein R is alkyl of three through eight .carbon atoms,cycloalkyl of four through nine carbon atoms, cycloalkylalkyl of fivethrough 10 carbon atoms, bicycloalkyl of seven through 10 carbon atomsor tricycloalkyl of 10 through 1 1 carbon atoms.

R is hydrogen, methyl or ethyl;

R is alkyl of three through eight carbon atoms, cycloalkyl of fourthrough nine carbon atoms, cycloalkylalkyl of five through 10 carbonatoms, bicycloalkyl of seven through 10 carbon atoms, or tricycloalkylof 10 through ll carbon atoms, with the limitation that the 1 and 4groups on the cyclohexyl ring must be in the cis configuration.

PREPARATION The animal repellant compounds are prepared using theintermediates of formulas (2) through (6) and the following syntheticroute:

R, R. and R in the following reactions are as defined above in formula 1o. RZCHZQJLL CH:

0 mom-@603; BNaOGl mcmQ-com v Pt mom-@4021: 3112 3C 2H mom-@4022:

o mom-@mziim vnr Those compounds where R is methyl or ethyl are preparedaccording to the following reactions where R becomes R during reaction-IX.

0 RZCHQ-NHPJR 1.1mm ether The Friedel-Crafts reaction (I) is run bycarefully adding the acid chloride toa stirring mixture of aluminumchloride and benzene. A slight molar excess of catalyst is used; benzeneserves as both a solvent and reactant. The acid chloride is added atsuch a rate so as to keep the temperature of the slurry at about 30-40C. The mixture is stirred for one additional hour after all of the acidchloride is added, and then water is slowly added to decompose thecatalyst. Sufficient water is added so that all the solids aredissolved. The phenylalkyl ketone is isolated from the benzene solutionand is purified by distillation.

The Wolff-Kishner reduction (II) is run in 2-(2- ethoxyethoxy)ethanolusing a modification of the procedure given by J. Cason, et al., inOrganic Synthesis, Collective Vol. IV, John Wiley and Sons, New York,(1963), p. 510. Once the reactants are mixed, they are heated to refluxfor a period of 3 to 5 hours. The reflux temperature is generally in the130-l40 C. range. After completion of the reflux period, the solution iscooled and poured into three to four volumes of water. The alkylbenzeneproduct is extracted with pentane and purified by distillation.

The Friedel-Crafts reaction (III) is run by mixing ap-v proximatelyequimolar quantities of the reactants together in hexane or nitromethaneat less than 5 C. The stirring 'mixture is slowly allowed to warm toroom temperature, and when hydrogen chloride evolution subsides, themixture is refluxed several hours. Water is then added slowly todecompose the catalyst. A sufficient quantity of water is then added sothat all of the cent Carbowax 20M on 60-80 meshDiatoport indicates thatabout 98 percent of the acetophenone is the 1,4 isomer and 2 percent isthe 1,2 isomer. The 1,2 isomer has the shorter retention time.

The haloform reaction (IV) is run by slowly adding a cold 5 C.) sodiumhypochlorite solution to a stirring solution of the acetophenonederivative in methanol.

This is a modification of the procedure used by E. E. Royals (J. Am.Chem. Soc., 69, 841 (1947) for the haloform reaction of a-ionone. Afterthe sodium hypochlorite solution is added, the mixture is warmed thesodium benzoate derivative remains dissolved;

however, when R becomes larger, such as bicycloheptyl the sodiumbenzoate derivative precipitates as a soapy solid. Sulfur dioxide isbubbled into the alkaline pot concentrate until the pH drops below 3.The precipitated benzoic acid derivative is either filtered and washedwith water, or extracted with methylene chloride depending on whether ornot the benzoic acid is easily filterable or is of a soapy nature. Someof these benzoic acid derivatives can be recrystallized from.acetonitrile or pentane, and some are purified merely by triturationwith cold pentane.

The catalytic hydrogenation (V) is performed at two to three atmospheresof hydrogen using platinum oxide as catalyst and glacial acetic acid assolvent. A Parr Hydrogenation Apparatus is suitable for these reactions.This reaction produces a cis/trans isomer mixture of about 2 or 3/1. Thecis and trans designation refers to the relationship of the 4-alkylsubstituent and carboxylic acid group on the cyclohexane ring, this isillustrated below com I -H &

cis

oom

RzCHz/ The Schmidt reaction (VI) is performed by dissolving thecyclohexane carboxylic acidderivative in a mixture of chloroform andconcentrated sulfuric acid. Sodium azide is then added in small portionsto the stirring mixture at a rate sufficient to keep the reactiontemperature between 35 and 45 C. The mixture is stirred at about 45 to50 C. until the bubbling nearly stops (1 to 3 hours). The mixture isthen transferred to a separatory funnel, and the lower, gelatinoussulfuric acid layer is slowly dripped onto ice. The amine sulfateprecipitates as a soapy material which slowly crystallizes. Thechloroform should be kept away from the ice water mixture since it makesthe work-up much more difficult. Those amines which crystallize as thehemisulfates orsulfates are filtered and washed with water.

It is convenient to store these amines as their salts. Those amine saltswhich fail to crystallize are converted to the free bases by making thesulfuric acid solution alkaline, and extracting the amine withdichloromethane. The amine is then purified by distillation. The Schmidtreaction proceeds without changing the cis/trans product ratio.

The acylation (VII) can be performed by dissolving the free amine in anequal volume of dimethylacetamide (DMAC) or dimethylformamide (DMF) andadding an excess of the desired acid anhydride to the stirring solution.This reaction is very exothermic. The solution is stirred for minutes,and then it is poured into 10 to 100 volumes of water. The amideseparates as an oil which subsequently crystallizes.

The acylation (VII) can also be performed using the amine sulfatedirectly according to the following procedure. The amine sulfate isground into a powder, and added to a 1:1 mixture of DMAC and 20 percentaqueous sodium hydroxide solution; there should be a large excess ofbase. The mixture is stirred for 10 to minutes, and then an excess ofthe desired acid anhydride is added. The mixture warms to about 60 to 65C. The sulfate entirely dissolves in 10 to minutes. The solution is thenpoured into 10 to 100 volumes of water. The amide is isolated by theusual procedures given above.

The formamides of reaction VIII are prepared by refluxing the amine withmethylformate for several hours. The excess methylformate is strippedfrom the reaction, and the residual formamide is purified byrecrystallization.

These acylations proceed without changing the cis/trans product ratio.

In those cases where R is methyl or ethyl, the formamide or acetamiderespectively is reduced by lithium aluminum hydride in refluxing etheraccording to reaction IX. The amine is isolated from the reaction afterthe lithium aluminum hydride is destroyed. These amines are purified bydistillation.

Reactions X and XI are run according to the procedures described forreactions VII and VIII respectively.

An alternative synthesis route can be used when the appropriatelysubstituted aniline derivatives are available. This route is illustratedbelow.

XII

mom-@mrm noogcm reflux III. 0 mom-@u-iln Reactions XIII and XIV areperformed according to reactions VII and VIII discussed above. Thecis/trans ratio for the amides from XII and XIII is about 1:1.

The pure amide isomers from reactions VII, VIII, X, XI, XIII and XIV canbe separated by chromatography over silicic acid using methylcyclohexanesaturated with acetonitrile as the eluting solvent. Isomer mixtures alsocan be separated by gas-liquid chromatography using 10 percent Carbowax20M on 60-80 mesh Diatoport T. In both of these chromatography methods,the cis isomer elutes before the trans isomer. The cis amine isomer canbe regenerated by alkaline hydrolysis of the purified amide.

The following additional examples describe the invention in greaterdetail.

EXAMPLE I A 23.9 gram quantity of 4-n-butylaniline (from AldrichChemical Company)'is dissolved in 250 milliliters of glacial aceticacid, and 1 gram of Adams Catalyst (PtO is added. The mixture is thenhydrogenated at 2 to 3 atmospheres using a Parr Hydrogenation Apparatus.To insure complete reduction, the hydrogenation is run over night. Thecatalyst is then filtered, and the acetic acid is removed under reducedpressure on a steam bath. The concentrate is taken up in ether andwashed with dilute, aqueous sodium bicarbonate. The ethereal solution isdried (MgSO filtered and evaporated in vacuum leaving 21 grams of the4-n-butylcyclohexylamine (n 1.4574). The amine is taken up in twovolumes of dimethylacetamide and treated with one volume of aceticanhydride. The temperature of the stirring solution rises rapidly to60-80 C. After having stirred for 10 minutes, the solution is pouredinto ten volumes of water. The oil which separates is extracted withether. The ethereal solution is dried (MgSO filtered and strippedleaving an oil which slowly crystallizes. This waxy solid softens at 57C. and melts from 79100 C. Gas-liquid chromatography of this cis/transmixture of N-acetyl-4-n-butylcyclohexylamine on an F & M Model 500 GasChromatograph over 10 percent Carbowax 20M on 60-80 mesh Diatoport T ina A inches X 2 feet stainless steel column at a temperature of 200 C., ablock temperature of 308 C., and an injection port temperature of 280 C.with a He flow rate of 60 cc./min. shows that the cisztrans ratio isabout 1:1.

The retention times for the cis and trans isomers are 28.0 and 32.5minutes respectively. The cis isomer causes severe burning of theoperators nose as it elutes from the column while the trans isomer doesnot cause much irritation.

The infra-red spectrum (nujol) for this mixture shows characteristicpeaks at 3300 cmfor the N-H, 1630 and 1560 cm for the amide carbonyl,1320 cm. for the trans isomer and 1280 cmfor the cis isomer.

Anal. Calcd. for C H NO: C, 73.0; H, 11.8; N,

7.1 percent Found: C, 72.9; H, 11.7;N, 6.7%

Mice are treated by aerosol exposure to the cis/trans mixture ofN-acetyl-4-n-butylcyclohexylamine in the following manner: The compoundis administered as an aerosol into a 2.8 liter chamber. The exposurechamber consists of a 2.8 liter bell jar over a nebullizer insertedthrough the floor of the chamber. Mice are exposed for five minutes to200.0 micrograms per liter (1,000Ct). The compound is dissolved in 1.4ml. of acetone and up into the chamber. No further air is transferredinto or out of the chamber during the five minute exposure.

After this exposure, irritant effects are observed in all mice exposed.The mice used as controls exposed to 1.4 ml. of acetone alone exhibit noirritant effects. Irritant effects can be described as the presence ofone or more of the following reactive signs:

a. hyperemia of the ears, nose and tail b. abnormal gait, includingrubbing of the nose the floor while running about c. blinking d.salivation e. depression f. dyspnea g. hunched posture h. face-pawing.

EXAMPLE 2 A mixture consisting of 400 ml. of benzene and 67 g. (0.5mole) of aluminum chloride is stirred in a 1 liter round bottom flaskfitted with a stirrer, thermometer condenser connected to a scrubber,dropped funnel, and cooling bath. Cyclobutane carbonyl chloride (50 g.;0.42 mole) is added dropwise while the pot temperature is held below 35C. The brown slurry is stirred for 1 hour and then water is cautiouslyadded while the pot temperature is held below 30 C. Sufficient water isadded so that all the solids dissolve. Two liquid phases are obtained.The mixture is transferred to a separatory funnel, and the benzene layeris separated. The aqueous layer is washed with 100 ml. of benzene whichis then combined with the first benzene fraction. The.

aqueous solution is discarded. The combined benzene fractions are washedsequentially with 200 ml. of 5 percent aqueous sodium hydroxide solutionand 250 ml. of water. The benzene solution is dried with magnesiumsulfate, filtered, and evaporated in vacuum. The residual oil isdistilled at 67 C. at 0.1 mm. of mercury giving cyclobutylphenylketone(111) 1.5455).

Anal. Calcd. for C H O: C, 82.5; H, 7.6 percent.

Found: C, 81.9; H, 7.6 percent.

EXAMPLES 3 The following phenylketone derivatives are prepared accordingto the procedures given for cyclobutylphen ylketone in Example 2 bysubstituting the appropriate molar amount of the acid chloride for thecyclobutane carbonyl chloride of Example 2. The acid chlorides areeither commercially available or easily prepared from the known acidwith thionylchloride.

3. 2-[2.2.l ]-Bicycloheptylphenylketone: B 98 C;n 1.5557. 4.Cyclopentylphenylketone: B, 130134 C.; n 1.5484 I 5.3-Cyclopentylpropiophenone: B 126 C.; n,, 1.5300

Anal. Calcd. for C H O: C, 83.2; H, 8.9 percent Found: C, 83.1; H, 8.9percent. 6. Cycloheptylphenylketone: B 134-l36 C.; n,, 1.5415

7. l-Adamantylphenylketone: m. 495 2 C. 8. 2-[2.2.2l-Bicyclooctylphenylketone 9. l-[ 3 .2. 1]-Bicyclooctylphenylketone 10. 2-[ 3.3 .1 ]-BicyclononylphenylketoneEXAMPLE 1 1 A solution of potassium hydroxide (140g; 2.5 mole) in 500ml. of 2-(2-ethoxyethoxyl)ethanol (from Matheson, Coleman & Bell Co.) isprepared by carefully heating the mixture until all of the solids aregone. The solution is cooled to below 100 C. Then 2-[2.2.1]-bicycloheptylphenylketone (94.7g'.; 0.50 mole) and 99 percent hydrazinehydrate l 10 g.; 2.2 mole) are added all at once. The reactants arerefluxed for 4 hours at 135 C., and then the solution is poured into 2.5l. of water. The oil which separates is extracted with three- 500 ml.portions of pentane. The aqueous phase is discarded, and the combinedpentane fractions are dried with magnesium sulfate, filtered andevaporated in vacuum. The residual oil is distilled at 120 C. at 12 mm.of mercury to give phenyl-2-[2.2.l]-bicyclohepty1methane(n,, 1.5342).

Anal. Calcd. for C I-1, C, 90.3; H, 9.7 percent Found: C, 90.8; H, 9.5percent EXAMPLES 12 22 17. 1-Adamantylphenylmethane: B 118-120 C.;'

n 1.5563; m. 37-4l C. Calcd. for C I-1 C, 90.2;

H, 9.8 percent.

Found: C, 89.5; H, 9.5 percent.

' 1s. 2-[2.2.21-Bicyclooctylphenylmethane.

1 9. 1-[ 3 2. l ]Bicyclooctylphenylmethane. 20. 2-[ 3.3.1]-Bicyclononylphenylmethane. 21 l-Homoadamantylphenylmethane.

22. 2-[ 3.2.0]-Bicycloheptylphenylmethane.

EXAMPLE 23 A solution of cyclobutylphenylmethane (20.5 g.; 0.14 mole)and acetyl chloride (12.5 g.;-0.l6 mole) in 400 ml. of hexane is cooledto 0 C. and aluminum chloride (21.5 g.; 0.16 mole) is added all at once.The reaction equipment is similar to that given in Example 2. Thestirring mixture'is warmed to about 5 C., and held there for a hour. Theslurry is then warmed to room temperature for one hour, and finallyrefluxed for 30 minutes. Water is then carefully added to decompose thealuminum chloride. Sufficient water is finally added to dissolve all thesolids and obtain two liquid phases The mixture is transferred to aseparatory funnel, and the hexane solution is isolated. The aqueousphase is washed with ml. of hexane, and then discarded. The combinedhexan'e fractions are washed sequentially with 100 ml. of 5 percentaqueous sodium hydroxide solution and 100 ml. of water. The hexanesolution is dried with magnesium sulfate, filtered and evaporatedinvacuum. The residual oil is distilled at 108 C. at 1 mm. of Hg to give4'-cyclobutylmethylacetophenone (n 1.5388).

Anal. Calcd. for C H o: C, 82.9; H, 8.6 percent.

Found: C, 83.1; H, 8.5 percent.

The pertinent features in the infra-red spectrum are a very strong peakat 1680 cm (carbonyl) and a peak at 850 cm indicative of two adjacentbenzenoid hydrogens thus showing that benzene ring has substituents inthe l and 4 positions.

A gas-liquid chromatogram obtained on an F & M Model 500 GasChr'omatograph using a 2 feet X A. inches O.D. Stainless Steel columnpacked with percent Carbowax 20M on 60-80 mesh Diatoport T with a heliumflow rate of 60cc/min. a block temperature of 307 C., an injection porttemperature of 262 C., and a column temperature of 225 C. shows that thesample consists of 98 percent of the 1,4-isomer and 2 percent of the1,2-isomer which have retention times of 9.5 and 8.0 minutesrespectively.

EXAMPLES 24 42 The following acetophenone derivatives are preparedaccording to the procedure given for 4'- cyclobutylmethylacetophenone inExample 23 by substituting a like amount of the appropriatealkylphenylmethane derivative for the cyclobutylphenylmethane of Example23. For those compounds where R is bior tricycloalkyl nitromethane canbe used as solvent in place of the hexane. The infra-red spectra for allthese compounds are similar to that reported for4'-cyclobutylmethylacetophenone in Example 23. 24.4-lsobutylacetophenone: B 1 10 C.; n 1.5156. 25. 4-n-Pentylacetophenone:B 122 C.; n 1.5142. 26. 4'-Cyclopentylmethylacetophenone: B 130- 132 C.;n 1.5394.

Calcd. for C H oz C, 83.2; H, 8.9 percent.

Found: C, 83.5; H, 8.9 percent.

Gas-liquid chromatography under conditions like those in Example 23 at acolumn temperature of 200 C. gives peaks at 14.0 minutes (2 percent ofsample) for the 1,2-isomer at 17.5 minutes (98 percent of sample) forthe 1,4-isomer.

27. 4'-(Z-Methylpentyl)acetophenone: B 96 C.; n 1.5120.

Anal. Calcd. for C H O: C, 82.3; H, 9.9 percent.

Found: C, 82.2; H, 9.8 percent.

Gas-liquid chromatography under conditions like those in Example 23gives peaks at 6.0 minutes (1 percent of sample) for the l,2isomer and7.5 minutes (99 percent of sample) for the 1,4-isomer. 28.4'-n-Hexylacetophenone: B n,,l.5106.

29. 4'Cyclohexylmethylacetophenone. 30. 4'-n-Heptylacetophenone: B130134 C.; n,, 1.5084. 31. 4'-n-Octylacetophenone: B 128 C.; n 1.5060.32. 4'-(3Cyclopentylpropyl)acetophenone: B 154 C.;n 1.5298.

Anal. Calcd. for C H O: C, 83.5; H, 9.6 percent.

Found: C,83.5;H,9.6percent. 33. 4'Cycloheptylmethylacetophenone: B 136140 C.; 11025 1.5426.

Anal. Calcd. for C H O: C, 83.4; H, 9.6 percent.

Found: C, 83.6; H, 9.7 percent. 34. 4'Cyclononylmethylacetophenone. 35.4Cyclooctylmethylacetophenone.

36. 4'-(2-[2.2.1]-Bicycloheptylmethyl)acetophenone: B ll7C.; n 1.5511.Anal. Calcd. for C H O: C, 84.2; H, 8.8 percent.

Found: C, 84.1; H, 8.8 percent. Gas-liquid chromatography underconditions like those given in Example 23 gives a single peak with aretention time of 29.5 minutes.

37. 4-( 1Adamantylmethyl)acetophenone. 38.4-(2-[2.2.2]-Bicyclooctylmethyl)acetophenone.

39. 4-(l-[3.2.1]-Bicyclooctylmethyl)acetophenone.

40. 4'-(2-[3.3.l ]Bicyclononylmethyl)acetophenone. 41. 4-(lHomoadamantylmethyl)acetophenone. 42.4-(2-[3.2.0]Bicycloheptylmethyl)acetophenone.

EXAMPLE 43 A solution of 4cyclobutylmethylacetophenone (20 g.; 0.11mole) in 225 ml. of methanol is cooled to less than 5 C., and 275 ml. ofa 1.29M sodium hypochlorite solution (0.35 moles) is slowly added. Thetemperature is held below 5 C. during the addition. The sodiumhypochlorite solution is conveniently preparedaccording to the proceduregiven by M. S. Newman, Organic Synthesis, Collective Volume 11, JohnWiley and Sons, New York, 1943, p. 429. After about 25 ml. of thehypochlorite solution is added, a white precipitate forms. When all ofthe hypochlorite solution is added, the stirring mixture is allowed towarm to room temperature, and left standing over night. Some chloroformusually separates during the night. The stirring mixture is heated toreflux C.) and distillate (200 ml.) is collected until the pottemperature rises above C. The pot concentrate is cooled to roomtemperature, and sulfur dioxide is bubbled into it until the pH fallsbelow 3. The precipitate is extracted with two-300 ml. portions ofdichloromethane, and the aqueous phase is discarded. The combineddichloromethane solutions are dried with magnesium sulfate, filtered andevaporated in vacuum. The yellow residue is triturated with coldpentane, and filtered. The 4-cyclobutylmethylbenzoic acid melts at146-149 C. and has an infra-red spectrum showing typical benzoic acidabsorption peaks.

Anal. Calcd. for C H 0 C, 75.8; H, 7.4 percent.

Found: C, 75.5; H, 7.6 percent.

Calcd. neutral equivalent weight: Found: 198

EXAMPLES 44 62 The following 4-alkylbenzoic acid derivatives areprepared according to the procedure given for 4- cyclobutylmethylbenzoicacid in Example 43 by substituting the appropriate 4'-alkylacetophenonein a like molar amount for the 4'-cyclobutylmethylacetophenone ofExample 43. All of these compounds show the typical benzoic acidabsorption peaks in their infra-red spectra.

44. 4-lsobutylbenzoic acid: m. l43.0l44.5 C.

Anal. Calcd. for C H O C, 74.2; H, 7.9 percent.

Found: C, 74.2; H, 7.9%. 45. 4-n-Pentylbenzoic Acid: m. 87.088.5 C. 46.4-Cyclopentylmethylbenzoic acid: m. l43.0-145.0 C.

Anal. Calcd. for C H O C, 76.5; H, 7.9 percent Found: C, 76.1; H, 7.5percent. 47. 4-(2-Methylpentyl)benzoic acid: m. l03-1 10 C.

Anal. Calcd. for C H O C, 75.7; H, 8.8 percent.

Found: C, 75.9; H, 8.9 percent. 48. 4-n-Hexylbenzoic acid. In. 77-82 C.49. 4Cyclohexylmethylbenzoic acid. I 50. 4-n-Heptylbenzoic acid: m.93-96 C. 51. 4-n-Octylbenzoic acid: m. 9698 C. 52. 4-(3Cyclopentylpropyl)benzoic acid: m. l l7l 19 C.

Anal. Calcd. for C l-l O C, 77.5; H, 8.7 percent. e n 97 t1 8-7Beret-int- 53. 4-Cycloheptylmethylbenzoic acid: m. 17l-173 C.

Anal. Calcd. for C H O C, 77.5; H, 8.7 percent.

Found: C, 77.2;H, 8.7 percent. 54. 4-Cyclooctylmethylbenzoic acid. 55.4-Cyclonony1methylbenzoic acid. 56.4-(2-[2.2.1l-Bicycloheptylmethyl)benzoic acid: m. l 7 l173 C.

Anal. Calcd. for c,,u,,o,: C, 78.3; H, 7.9 percent Found: C, 77.6; H,7.9 percent. Calcd. neutral equivalent weight:

Found: 243. 57. 4-(1-Adamantylmethyl)benzoic acid. 58.4-(2-[2.2.2]-Bicyclooctylmethy1)benzoic acid. 59. 4-( 1-[ 3.2. 1]-Bicyclooctylmethyl)benzoic acid. 60. 4-(2-[ 3 .3. l]-Bicyclononylmethyl)benzoic acid. 61 4-( 1-Homoadamantylmethyl)benzoicacid. 62. 4-( 2-[ 3.2.0]-Bicycloheptylmethyl)benzoic acid.

EXAMPLE 63 A sample of 4-cyclobutylmethylbenzoic acid (8.3 g.;0.044mo1e) is dissolved in 250 ml. of glacial acetic acid in a 500 ml.pressure bottle and platinum oxide (1 g.) is added. The mixture is thenshaken under a hydrogen pressure of 45 p.s.i.g. on a Parr HydrogenationApparatus for 24. hours; the final pressure is 33 p.s.i.g. The catalystis filtered, and the acetic acid removed in vacuum. The residual oil istaken up in 200 ml. of ether, and washed with two-100 ml. portions ofwater to remove the residual acetic acid. The ethereal solution is thendried with magnesium sulfate, filtered and evaporated in vacuum leavingan oil which subsequently crystallizes. The 4-cyclobutylmethy1-cyclohexane carboxylic acid is recrystallized from a mixture of ethanoland water, and melts from 59 to 69 C. The cis/trans mixture ofcarboxylic acids causes the broad melting range.

Anal. Calcd. for C H O cent Found: C, 73.4; H, 10.2 percent.

The infra-red spectrum shows that the benzene ring has been reduced.

EXAMPLES 64 82 The following 4-alkylcyclohexane carboxylic acidderivatives are prepared according to the procedure givenfor4-cyclobutylmethylcyclohexane carboxylic acid in Example 63 bysubstituting the appropriate 4-alkylbenzoic acid in a like molar amountfor the 4- cyclobutylmethylbenzoic acid of Example 63. Infra-red spectraof these compounds also show that the benzene rings have been reduced.

64. 4-lsobutylcyclohexane carboxylic acid: B 118- 119 C.; N 1.4638.

Anal. Calc d. f! (31 112002:

cent Found: C, 72.3; H, 1 1.3 percent. 65. 4-n-Pentylcyclohexanecarboxylic acid: B 138 C.; n,, 1.4652. Anal. Calcd. for C H O C, 72.8;H, 11.2 percent. Found: C,..72.8; H, 11.4 percent. 66.4-Cyclopentylmethylcyclohexane carboxylic acid; B 140C; n 1.4910,m. 3847C.

Anal. Calcd'for C, H O C, 74.2; H, 10.5 percent Found: C, 73.9; H, 10.7percent. 67. 4-(2-Methylpentyl)cyclohexane carboxylic acid:

C, 73.5; H, 10.2 per- C, 71.7; H, 10.9 per- C, 73.5; H, 11.3 per- C,73.4; H, 11.4 per- C, 74.9; H, 10.8 per- 70. 4-n-Heptylcyclohexanecarboxylic acid: B

Anal. Calcd. for C H O z cent. Found: C, 74.5; H, 11.4 percent.

71. 4-n-Octylcyclohexane carboxylic acid: m. 3639 C. (from acetonitrile)Anal. Calc d. for CuHjgOgl cent.

Found: C, 75.5; H, 11.9 percent. 72. 4-( 3-Cyclopentylpropyl)cyclohexanecarboxylic acid: B 163 C.; n 1.4872.

cent.

Found: C, 75.4; H, 10.8 percent. 73. 4-Cycloheptylmethylcyclohexanecarboxylic acid; B l60-162 C.; n l .4963; m. 45-49 C. Calcd. for C I-1 0C, 75.5; H, 11.0 percent. Found: C, 75.5; H, 10.8 percent. NeutralEquivalent: Calcd. 238. Found: 238. 74. 4-n-Nony1cyclohexane carboxylicacid. 75. 4-Cyclonony1methylcyclohexane carboxylic acid. 76.4-(2-[2.2.1]-Bicycloheptylmethyl)cyclohexane carboxylic acid: m. 64-73C. (from ethanol).

Anal. Calcd. for C H O C, 76.2; H, 10.2 percent.

Found: C, 76.1; H, 10.1 percent. 77. 4-(1-Adamantylmethyl)cyclohexanecarboxylic acid. 78. 4-(2-[2.2.2]-Bicyclooctylmethyl)cyclohexanecarboxylic acid. 79. 4-(1-[3.2.1l-Bicyclooctylmethyl)cyclohexane.carboxylic acid.

C, 74.3; H, 11.6 per- C. 75.0; H, 11.4 per- C, 75.5; H, 11.0 per 80.4-(2-[3.3. 1 ]-Bicyclononylmethyl)cyclohexane carboxylic acid.

81 4-( 1-Homoadamantylmethyl)cyclohexane carboxylic acid.

82. 4-(2-[3.2.0]-Bicycloheptylmethyl)cyclohexane carboxylic acid.

EXAMPLE 83 A sample of 4-n-hexylcyclohexane carboxylic acid (24 g.; 0.11 mole) is taken up in a mixture of 200 ml. of chloroform and 1 10 ml.of concentrated sulfuric acid in a 500 ml. Erlenmeyer flask. Sodiumazide (9.8 g.; 0.15 mole) is carefully added with a spatula at a rate tokeep the temperature of the stirring mixture between 35 and 45 C. Aftercompletion of the sodium azide addition, the stirring mixture is heatedat 45-50 C. for 2 hours; the rate of gas evolution is very slow at thistime. The mixture is transferred to a separating funnel and the lower,gelatinous sulfuric acid layer is slowly dripped into one liter ofcrushed ice. The 4-n-hexyl- EXAMPLES 84 102 The following4-alkylcyclohexylamine derivatives or their salts are prepared accordingto the procedure given for 4-n-hexylcyclohexylamine hemi-sulfate inExample 83 by substituting the appropriate 4-a1ky1- cyclohexanecarboxylic acid in like amount by weight for the 4-n-hexylcyc1ohexanecarboxylic acid ofExample 83. In those instances where the free aminesare prepared, the amine salt is dissolved in percent aqueous sodiumhydroxide solution, and the free amine is extracted withdichloromethane. The dichloromethane solution is dried with magnesiumsulfate, filtered and evaporated in vacuum. The residual oil isdistilled in vacuum through a spinning band column. The infra-redspectra of these compounds all show the loss of the carbonyl functionand the presence of an amino function.

84. 4-lsobutylcyclohexylamine: Bl.456 C.; n 25 Anal. Calcd. for C H N:C, 77.4; H, 13.6; N, 9.0

percent Found: C, 77.6; H, 13.5; N, 9.1 percent. 85.4-n-Pentylcyclohexylamine: B 76 C.; n 1.4612.

Anal. Calcd. for C H Nz C, 78.0; H, 13.7; N, 8.3

percent.

Found: C, 77.9; H, 13.6; N, 8.6 percent. 86.4-Cyclopentylmethylcyclohexylamine hemi-sulfate: m. 300 C.

Anal. Calcd. for C H N'BQH SO 10.5; N,6.1 percent. Found: C, 62.0; H,10.7; N, 6.0 percent. 87. 4-( 2-Methylpentyl)cyclohexylamine: B, 808lC.; n n 1.4625.

Anal. Calcd. for C H N: C, 78.7; 13.7; N, 7.6

percent. Found: C, 78.3; H, 13.7; N, 8.1 percent. 88.4-Cyclobutylmethylcyclohexylamine.

.89. 4-cis-Cyclohexylmethylcyclohexylamine hemisulfate: in. 300C.

Anal. Calcd. for C, H N%H SO C, 64.0; H,

10.8; S, 6.6 percent.

Found: C, 55.2; H, 9.8N, 4.5; S.'9.9 percent. 93.4-Cycloheptylmethylcyclohexylamine hemi-sulfate: m 300 C. 94.4-Cyc1ooctylmethylcyclohexylamine hemi-sulfate: m 300 C. v 95.4-Cyclononylmethylcyclohexylamine hemi-sulfate: m 300 C. 96. 4-(2-[2.2.1]-Bicycloheptylmethyl)cyclohexylami ne hemi-sulfate dihydrate: m. 300 C.Calcd. for C HgsNC H25N'%H2S04'2H20i C, ['l, N, 4.8'percent. Found: C,58.5; H, 9.3; N, 4.7 percent. 97. 4-(l-Adamantylmethyl)cyclohexylaminesulfate: m. 300 C.

98. 4-(2-[2.2.2]-Bicyclooctylmethyl)cyclohexylamine Anal. Calcd. for C HN'H SO C, 54.6; H, 9.5;

sulfate: m. 300 C. 99. 4-( 1-[ 3 .2.1]-Bicyclooctylmethyl)cyclohexylamine sulfate: m. 300 C. 100.4-(2-[3.3.1]-Bicyclononylmethyl)cyclohexylamin e hemi-sulfate: m. 300 C.101 4-( 1-Homoadamantylmethyl)cyclohexylamine sulfate: m. 300 C. 102.4-( 2-[ 3 .2.0I-Bicycloheptylmethyl)cyclohexylami ne hemi-sulfate: m.300 C. V

. EXAMPLE.

A sample of 4-n-hexylcyclohexylamine hemi-sulfate (10 g.; 0.043 mole) isstirred for ten minutes in a mixture consisting of 100 ml. ofdimethylacetamide and '25 ml. of 20 percent aqueous sodium hydroxidesolution. Acetic anhydride (20 ml.) is added with stirring; thetemperature rises to -'80 C. After the temperature has dropped to about60 C., the milky suspension is filtered to remove any traces ofunreacted 4-n-hexylcyclohexylamine hemi-sulfate. The milky filtrate ispoured into 1200 ml. of water, and the oil which separates crystallizes.The crystalline N-acety1-4-n-hexylcyclohexylamine is filtered and washedwith water. It melts from 49 to 87 C.

Anal. Calcd. for C H NO: C, 74.8; N, 12.1; N,

6.2 percent.

Found: C, 74.7; H, 12.0; N, 6.3 percent.

Gas-liquid chromatography on an F & M Model 500 Gas Chromatograph usinga 2 inch X A inches O.D. stainless steel column packed with 10 percentCarbowax 20M on 60-80 mesh Diatoport T at a column temperature of 200C., a block temperature of 308 -C. an injection port temperature of 265C. and a helium flow rate of 60 cc/min. shows'that the sample consistsof two compounds present to the extent of 64pe'rcent and 36 percentwhich have retention times of 53.3 and 61.8 minutes respectively.

A nuclear magnetic resonance spectrum of the mixture shows that thelarger component is N-acetyl-cis-4- n-hexylcyclohexylamine and thesmaller component is N-acetyltrans-4-n-hexylcyclohexylamine.

The pure isomers are isolated by adsorption chromatography over silicicacid using methylcyclohexane saturated with acetonitrile as the elutingsolvent; the adsorbent to compound ratio is 50:1.N-Acetyl-cis-4-nhexylcyclohexylamine melts at 550 to 570 C., andN-acetyl-trans-4-n-hexylcyclohexylamine melts at 123.0-124.0 C.

The cis/trans mixtures are used for the purposes of this inventionwithout separation of the isomers.

N-Acetyl-4-n-hexylcyclohexylamines are used to treat mice according tothe procedures given in Example 1 with like results. At the time mi'c eare treated in such manner with the pure isomers, the cis isomer isshown to be much more of an irritant than the trans isomer.

EXAMPLES 104- 125 The following N acyl-4-alkylcyclohexylamines areprepared according to the procedure given for N-acetyl-4-n-hexylcyclohexylamine in Example'l03 by substituting in a likemolar amount the appropriate 4- alkylcyclohexylamine and acid anhydridefor the 4-nhexylcyclohexylamine and acetic anhydride of Example 103.104. N-Acetyl-4-isobutylcyclohexylamine: m. 96-1 18 C, cis/trans ratio=63('41.0 min./37 (47.2 min.) by G.L.C. method like that in Example 103at a column temperature of 180C.

Anal. Calcd..for C H NO: C, 73.0: H, 11.7; N,

N, 6.2 per- 109. ylamine. 1 l0. N-Acetyl-4-(2-methylpentyl)cyclohexylamine: m. 58-69 C. cis/trans ratio=87(54.5min.)/13(62.6min.) by G.L.C. method similar to that in Example.103 at a column temperature of 190 C.

Calcd. for C HQQNO: C, 74.7; H, 12.1; N, 6.2 percent. Found: C, 74.6; H,l 1.9; N, 6.0 percent. 1 l l. m. 4259 C. cis/trans ratio=78(43.5min)/22(49. 6min) bya G.L.C. method like that in Example 103 ata column temperature of 200 C.

Calcd. for C H NO: C, 74.7; H, 11.1; N, 6.7 percent.

Found: C, 74.7; H, 11.1; N, 6.5 percent.

112. N-Acetyl-4-n-heptylcyclohexylamine; m. 6l'1l4 C., cis/trans ratio64(23.5min.)/36(27.0min.) by a G. L. C. method like that in Example 103at a col. temperature of 230 C.

Calcd. forC H NO: C, 75.3; H, 12.2; N, 5.9 percent. Found: C, 75.0; H,12.1; N, 5.9 percent. 1 13. N-Acetyl-4-n-octylcyclohexylamine; m. 6282C. cis/trans ratio 75(31.5min.)/25(36.5min.) by a G. L. C. methodsimilar to that of Example 1 12.

Calcd. for C H NO: C, 76.0; H, 12.3; N, 5.5 percent. Found: C, 75.8;-H,12.3; N, 5.4 percent. 1 l7. N-Acetyl-4-cyclooctylmethylcyclohexylamine.1 18. N-Acetyl-4-cyclononymethylcyclohexylamine.

N-Acetyl-4-Cyclobutylmethylcyclohexylamine:

1 19. N-Acetyl-4-t2-[2.2. 1 ]-bicycloheptylmethyl)cyclohexylamine: m.l1l-l13 C. cis/trans ratio 73(55.8min.)/27(63.5min.) by G.L.C. methodlike that in Example 103 at a column temperature of 225 C.

Calc'd. for C H NO: C, 77.2; H, 10.9; N, 5.6 percent. Found: C, 76.9; H,10.7; N, 5.6 percent.

120. N-Acetyl-4-( 1-adamantylmethyl)cyclohexylamine. 121 N-Acetyl-4-(2-[2.2.2]-bicyc1ooctyl- EXAMPLE 126 A sample of4-cyclobutylmethylcyclohexylamine (10 g.; 0.060 mole) is refluxed forthree hours with 20 ml. of methylformate. The solution is thenevaporated in vacuum and the residualN-formyl-4-cyclobutylmethylcyclohexylamine is purified byrecrystallization from hexane. ThisN-formyl-4-cyclobutylmethylcyclohexylamine is used to treat mice andother animals according to the procedures given in US. Pat. applicationSer. No. 532,544, filed March 1, 1966, now abandoned.

EXAMPLE 12 7 A mixture of N-formyl-4-cyclohexylmethylcyclohexylamine(7.9g.; 0.035 mole) and lithium aluminum hydride (LAH) (3.8g.; 0.10mole)is heated in ml. of refluxing ether for 24 hours. The suspension iscooled, and the lithium aluminum hydride is decomposed using wet etherand then a saturated, aqueous solution of sodium sulfate. Thisdecomposition should be performed cautiously to avoid a fire. Theprecipitated salts are filtered and washed with ether. The etherealsolution is then dried with magnesium sulfate, filtered and evaporatedin vacuum learving an oil. The infra-red spectrum shows the oil to be anamine. The N-methyl-N-cyclohexylmethylcyclohexylamine is purified byvacuum distillation.

EXAMPLES 128-141 133. N-Ethyl-N-[4-( 2-[2.2.1 ]-bicycloheptyl-N-Methyl-N-(4-cyclobutylmethylcyclohex- EXAMPLES 142 156 The followingN-acyl-N-methyl or ethyl-N-4-alkylcyclohexylamine derivatives areprepared according to the directions given for preparingN-acetyl-4-n-hexylcyclohexyamine in Example 103 or N-formyl-4-cyclobutylmethylcyclohexylamine in Example 126 by substituting theobvious reactants in like molar amount by weight for those given inExamples 103 and 126. 142. N-Acetyl-N-methyl-N-(4-cyclobuty1methylcyclohexyhamine.

143. N-Acetyl-N-ethyl-N-( 4-n-butylcyclohexyl)amine.

N-Methyl-N-( 4-cycloheptylmethylcyclohex- N-Ethyl-N-[4-(l-adamantylmethyl)cyclohexyl] 144.N-Formyl-N-methyl-N-(4-n-hexylcyclohexyl )amine. 145.N-Formyl-N-ethyl-N-(4-cyclopentylmethylcyclohexyl)amine. 146.N-Propionyl-N-methyl-N-(4-cycloheptylmethylcyclohexyl)-amine. 147.N-Butanoyl-N-methyl-N-(4-cyclononylmethylcyclohexyl)amine.

148. N-Acetyl-N-ethy1-N-( 4-n-pentylcyclohexyl)amine.

149. N-Acetyl-N-methyl-N-(4-n-heptylcyclohexyl)amine.

150. N-Acetyl-N-ethyl-N-[4-(2-methylpentyl)cyclohexyl]amine.

l5 1 N-Butanoyl-N-methyl-N-(4-isobutylcyclohexylamine.

152. N-Formyl-N-ethyl-N-(4-n-octylcyclohexyl)amine.

l 53. N-Formyl-N-methyl-N-[4-(2-[ 2.2. ll-bicycloheptylmethyl)-cyclohexyl]amine.

154. N-Acetyl-N-ethyl-N-[4-( l-adamantylmethyl)cyclohexyl]-amine.

155. N-Acetyl-N-methyl-N-[4-( l-homoadamantylmethyl)cyclohexyl]-amine.

156. N-Acetyl-N-methyl-N-[4-(2-[ 3.3.1bicyclononylmethyl)-cyclohexyl]amine.

I claim: 1. A compound of the formula:

mom-@mm wherein R is selected from the group consisting of hydrogen,

methyl and ethyl, and R is alkyl of three through six carbon atoms,cycloalkyl of four through nine carbon atoms, cycloalkylalkyl of fivethrough 10 carbon atoms, bicycloalkyl of seven through 10 carbon atomsand tricycloalkyl of 10 through 11 carbon atoms; with the limitationthat the 1 and 4 groups on the cyclohexyl ring must be in the cisconfiguration. 2. A compound according to claim 1 which is4-cis-nhexylcyclohexylamine.

3. A compound according to claim 1 which is4-ciscyclohexylmethylcyclohexylamine.

4. A compound according to claim 1 which is4-ciscyclopentylmethylcyclohexylamine.

5. A compound according to claim 1 which is 4-cis-nbutylcyclohexylamine.

6. A compound according to claim 1 which is N-4-cis-cyclohexylmethylcyclohexyl-N-methylamine.

7. A compound according to claim 1 which is 4-cisc clohe t lmeth lcclohex lamine.

8. A oi' npouni i according to claim 1 which is 4-cis-

2. A compound according to claim 1 which is4-cis-n-hexylcyclohexylamine.
 3. A compound according to claim 1 whichis 4-cis-cyclohexylmethylcyclohexylamine.
 4. A compound according toclaim 1 which is 4-cis-cyclopentylmethylcyclohexylamine.
 5. A compoundaccording to claim 1 which is 4-cis-n-butylcyclohexylamine.
 6. Acompound according to claim 1 which isN-4-cis-cyclohexylmethylcyclohexyl-N-methylamine.
 7. A compoundaccording to claim 1 which is 4-cis-cycloheptylmethylcyclohexylamine. 8.A compound according to claim 1 which is4-cis-(2-(2.2.1)-bicycloheptylmethyl)cyclohexylamine.
 9. A compoundaccording to claim 1 which is 4-cis-(1-adamantylmethyl)cyclohexylamine.10. A compound according to claim 1 which is4-cis-(3-cyclopentylpropyl)cyclohexylamine.